PCBP1-AS1 facilitates liver metastasis in pancreatic cancer by modulating miR-125b-5p in Tumor-derived exosomes to target TNFAIP3

Background: To investigate the role of PCBP1-AS1 in pancreatic cancer (PCa) liver metastasis and its underlying mechanisms.

Methods: We analyzed the expression patterns of PCBP1-AS1, miR-125b-5p, and TNFAIP3 in PCa tissues, normal tissues, and peripheral blood exosomes. The relationships between these molecules and PCa pathological features, including liver metastasis, were examined. Dual-luciferase reporter assays confirmed the targeting interactions among PCBP1-AS1, miR-125b-5p, and TNFAIP3. We constructed PCa cell lines overexpressing miR-125b-5p and/or TNFAIP3, as well as PCBP1-AS1 and/or miR-125b-5p, to assess their effects on TNFAIP3 expression and cellular behaviors. The impact of exosomes from transfected or untransfected PCa cells on TNFAIP3 levels, NF-κB activation, and hepatic stellate cells (HSCs) to cancer-associated fibroblasts (CAFs) transformation was evaluated. A PCa liver metastasis model was constructed to study the effects of exosomes on HSCs activation.

Results: MiR-125b-5p was largely upregulated in PCa tissues and peripheral blood exosomes, with high expression correlating with advanced disease stage and liver metastasis. MiR-125b-5p promoted PCa progression by targeting TNFAIP3. Overexpression of miR-125b-5p further enhanced TNFAIP3 suppression, p-p65 activation, and HSCs-to-CAFs transformation induced by PCa-derived exosomes, while miR-125b-5p inhibition reversed these effects. Preconditioning with PCa-derived exosomes facilitated liver metastasis in vivo, with increased miR-125b-5p levels exacerbating metastasis by targeting TNFAIP3 and activating NF-κB. Reduced PCBP1-AS1 expression was associated with poorer survival in PCa patients and was significantly lower in tissues from patients with liver metastases. PCBP1-AS1 counteracted miR-125b-5p-mediated TNFAIP3 suppression and mitigated the tumor-promoting effects of miR-125b-5p.

Conclusions: PCBP1-AS1 enhances TNFAIP3 expression by targeting miR-125b-5p, thereby inhibiting PCa progression. Reduced PCBP1-AS1 in PCa increases miR-125b-5p levels in exosomes, activating NF-κB and promoting HSCs-to-CAFs transformation, creating a favorable microenvironment for liver metastasis.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12885-025-14854-x.